Ically changed solvents, temperature, and base, screened zinc and copper catalysts, and tested various chloroformates

Ically changed solvents, temperature, and base, screened zinc and copper catalysts, and tested various chloroformates at varying amounts to activate the pyridine ring for any nucleophilic ynamide attack. We found that quantitative conversion might be accomplished for the reaction between pyridine and ynesulfonamide 1 utilizing copper(I) iodide as catalyst and two equiv of diisopropylethylamine in dichloromethane at room temperature. The heterocycle activation demands the presence of 2 equiv of ethyl chloroformate; the general reaction is drastically quicker when five equiv is used, but this has no effect on the isolated yields. Replacement of ethyl chloroformate with the methyl or benzyl derivative proved MFAP4 Protein supplier detrimental towards the conversion. Using our optimized procedure with ethyl chloroformate and 2 equiv of base, we had been in a position to isolate ten in 71 yield following 2.5 h at space temperature; see entry 1 in Table 2. We then applied our catalytic process to many pyridine analogues and obtained the corresponding 1,2-dihydropyridines 11-14 in 72-96 yield, entries 2-5. The coppercatalyzed ynamide addition to activated pyridines and quinolines generally shows quantitative conversion, but the yield from the preferred 1,2-dihydro-2-(2-aminoethynyl)heterocycles is in some situations compromised by concomitant formation of noticeable amounts on the 1,4-regioisomer. With pyridine substrates we observed that the ratio from the 1,2versus the 1,4-addition product varied between 3:1 and 7:1 unless the para-position was blocked, whilst solvents (acetonitrile, N-methylpyrrolidinone, acetone, nitromethane, tetrahydrofuran, chloroform, and dichloromethane) and temperature alterations (-78 to 25 ) had literally no impact around the regioselectivity but affected the conversion of this reaction.19 The 1,2-dihydropyridine generated from 4methoxypyridine rapidly hydrolyses upon acidic workup and careful chromatographic purification on basic alumina gave ketone 15 in 78 yield, entry 6. It is noteworthy that the synthesis of functionalized piperidinones for example 15 has become increasingly critical on account of the use of these versatile intermediates in medicinal chemistry.18a We were pleased to locate that our technique can also be applied to quinolines. The ynamide addition to quinoline gave Nethoxyarbonyl-1,2-dihydro-2-(N-phenyl-N-tosylaminoethynyl)quinoline, 16, in 91 yield, entry 7 in Table 2. In contrast to pyridines, the reaction with quinolines apparently happens with high 1,2-regioselectivity and no sign from the 1,4-addition solution was observed. Ultimately, 4,7-dichloro- and 4-chloro-6methoxyquinoline had been converted to 17 and 18 with 82-88 yield and 19 was obtained in 95 yield from phenanthridine, entries 8-10. In analogy to metal-catalyzed nucleophilic additions with alkynes, we think that side-on coordination in the ynamide to copper(I) increases the acidity with the terminal CH bond. Deprotonation by the tertiary amine base then produces a copper complex that reacts together with the electrophilic acyl Cathepsin S Protein Molecular Weight chloride or activated N-heterocycle and regenerates the catalyst, Figure 3. The ynamide additions are sluggish within the absence of CuI. We found that the synthesis of aminoynone, 2, from 1 and benzoyl chloride is almost total right after ten h, but much less than 50 ynamide consumption and formation of unidentified byproducts have been observed when the reaction was performedNoteTable two. Copper(I)-Catalyzed Ynamide Addition to Activated Pyridines and QuinolonesaIsolated yield.devoid of the catalyst. NMR monitoring of your ca.